ALS Disease Involves Cells Other Than Motor Neurons

A new study of mice finds that cells other than motor neurons play a bigger role in the development of the fatal degenerative disease
amyotrophic lateral sclerosis (ALS) than first thought. It shows that the cells that produce the myelin insulation that protects nerve cells may play
a key role. If confirmed, this would suggest ALS has more in common with multiple scleroris (MS) than previously thought.

Writing about their discovery in the 31 March online issue of Nature Neuroscience, the researchers suggest it may lead to new drug targets
for slowing or stopping disease progress.

Co-author Jeffrey D. Rothstein, a professor of neurology at Johns Hopkins University School of Medicine, in Baltimore, Maryland, US, and
colleagues found that abnormalities in a group of cells known as oligodendrocytes appear to have a profound effect on the survival of motor
neurons.

Oligodendrocytes Support Neurons

In ALS, also known as motor neuron disease (MND) or Lou Gehrig's disease, the motor neurons (nerve cells that control movement) in the brain
and spinal cord waste away and die, gradually causing the person to lose their ability to move and also, eventually, breathe.

Oligodendrocytes are cells located near motor neurons that support the neurons and produce the myelin sheath that covers and insulates them so signals to and from muscles can be sent quickly, without losing strength.

For a long time, scientists believed oligodendrocytes only provided structural support for the various nerve cells that transport the signals to and from the
central nervous system. However, more recently, they have been finding this may not be the case, but the exact nature of their bigger role has not been clear.

In another recent study, Rothstein and others found that oligodendrocytes keep neurons fed with essential nutrients that are vital for their survival.

Oligodendrocytes Have Essential Role In the Early Stages of ALS

In this latest study, Rothstein and colleagues examined mice bred with a gene mutation that causes ALS in humans, and discovered some profound
changes in their oligodendrocytes that emerged long before symptoms of the disease.

They found that the oligodendrocytes in the ALS mice died off at very high rates, and new ones made to replace them were inferior and did not
work properly.

"Although new oligodendrocytes were formed, they failed to mature, resulting in progressive demyelination," they write.

In another set of experiments, the researchers looked at brain tissue samples from 35 people who died of ALS and found similar changes to those seen in the mice:

"Oligodendrocyte dysfunction was also prevalent in human ALS, as gray matter demyelination and reactive changes in NG2+ cells were
observed in motor cortex and spinal cord of ALS patients," they note.

Rothstein says it may be possible to look for these changes in patients in early stages of the disease and use MRI technology to follow
progression.

He and his colleagues then did another experiment where they bred mice with an active ALS gene in their motor neurons, but switched the gene off
in their oligodendrocytes.

To their surprise, this combination profoundly delayed onset of ALS. The mice also lived some three months longer, which is a long time in their
lifespan.

These important sets of results led the researchers to conclude that oligodendrocytes play an essential role in the early stages of ALS.

Damage to Oligodendrocytes Potential Marker for Disease Progression

Rothstein, who is also director of the Johns Hopkins Medicine Brain Science Institute, says in a statement that the findings show that cells we never
thought played an important part in ALS are not only involved, but contribute to the start of the disease.

Co-author Dwight E. Bergles, a professor of neuroscience at the Johns Hopkins, adds:

"The motor neurons seem to be dependent on healthy oligodendrocytes for survival, something we didn't appreciate before."

Rothstein says if further studies confirm these findings, "perhaps we can start looking at ALS patients in a different way, looking for damage to
oligodendrocytes as a marker for disease progression".

"This could not only lead to new treatment targets but also help us to monitor whether the treatments we offer are actually working," he adds.

ALS May Share Common Ground with MS

The researchers believe these findings also open the possibility that ALS may have more in common with multiple scleroris (MS), where the myelin
insulation around neurons wastes away, than previously thought.

Bergles says MS researchers have been looking closely at oligodendrocytes. In MS, over time the disease can change from the remitting-relapsing
form, where myelin is attacked but then regrows as progenitor cells create new oligodendrocytes, to a more chronic form, where oligodendrocytes
are no longer regenerated.

MS researchers are searching for ways to restore the regeneration of new oligodendrocytes as a possible treatment approach.

"It's possible that we may be able to dovetail with some of the same therapeutics to slow the progression of ALS," says Bergles.

Grants from the National Institutes of Health's National Institute of Neurological Disorders and Stroke, the ALS Association, P2ALS, the Robert
Packard Center for ALS Research at Johns Hopkins and the Brain Science Institute, helped pay for the study.

In 2012, a systematic review of 11 studies published in the journal Science Translational Medicine suggests for the first time that it may be possible to use stem cell transplants to slow progression of ALS and
extent quality and length of life for patients.

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